Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant.

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is associated with dyslipidemia and cardiovascular disease (CVD). AIM: To determine the relationship between resolution of NASH and dyslipidemia. METHODS: Individuals in the Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial with paired liver biopsies and fasting lipid levels were included (N = 222). In the PIVENS trial individuals were randomised to pioglitazone 30 mg, vitamin E 800 IU or placebo for 96 weeks. Change in lipid levels at 96 weeks was compared between those with and without NASH resolution. RESULTS: Dyslipidemia at baseline was frequent, with low high-density lipoprotein (HDL) (<40 mg/dL in men or <50 mg/dL in women) in 63%, hypertriglyceridaemia (≥150 mg/dL) in 46%, hypercholesterolaemia (≥200 mg/dL) in 47% and triglycerides (TG)/HDL >5.0 in 25%. Low-density lipoprotein (LD) ≥160 mg/dL was found in 16% and elevated non-HDL cholesterol (non-HDL-C) (≥130 mg/dL) in 73%. HDL increased with NASH resolution but decreased in those without resolution (2.9 mg/dL vs. -2.5 mg/dL, P < 0.001). NASH resolution was associated with significant decreases in TG and TG/HDL ratio compared to those without resolution (TG: -21.1 vs. -2.3 mg/dL, P = 0.03 and TG/HDL: -0.7 vs. 0.1, P = 0.003). Non-HDL-C, LDL and cholesterol decreased over 96 weeks in both groups, but there was no significant difference between groups. Treatment group did not impact lipids. CONCLUSIONS: NASH resolution is associated with improvements in TG and HDL but not in other cardiovascular disease risk factors including LDL and non-HDL-C levels. Individuals with resolution of NASH may still be at increased risk of cardiovascular disease. ClinicalTrials.gov identifier: NCT00063622.

Neutralizing IL-17 prevents obliterative bronchiolitis in murine orthotopic lung transplantation.

Obliterative bronchiolitis (OB) is the key impediment to the long-term survival of lung transplant recipients and the lack of a robust preclinical model precludes examining OB immunopathogenesis. In the current study, lungs from C57BL/10 H-2(b) mice that are MHC compatible, but minor histocompatability antigen incompatible, were transplanted into C57BL/6 mice. Histological features and cytokine profiles of OB were assessed. Moderate rejection (grade A3) developed by day 14, with evidence of OB at that time point. At 21 days, OB was present in 55% of grafts and moderate to severe rejection (grade A3-A4) was present in all mice. At 28 days, OB was present in 44% of mice and severe rejection (grade A4) was present in all. IL-17A, but not IL-17F, splenic mRNA transcripts and serum protein levels were increased only in mice that developed OB, whereas IL-10 transcripts and protein were increased only in non-OB mice. Neutralizing IL-17 prevented OB, down regulated acute rejection, and upregulated systemic IL-10. Collectively, these data show that transplantation of minor histoincompatible lungs from C57BL/10 mice into C57BL/6 mice results in a highly reproducible preclinical model of OB. In addition, these data indicate that neutralizing IL-17A or augmenting IL-10 could be therapeutic interventions to prevent OB.

Silencing S1P1 receptors regulates collagen-V reactive lymphocyte-mediated immunobiology in the transplanted lung.

Type V collagen (col[V])-reactive lymphocytes contribute to lung transplant rejection, but the mechanisms for emigration into the graft are unknown. Sphingosine-1-phosphate-1 receptors (S1P(1R)) are believed to be required for lymphocyte emigration in other studies, but their role in col(V)-reactive lymphocyte rejection responses is not known. Utilizing small interfering RNA (siRNA) to reduce S1P(1R) expression on col(V)-reactive lymphocytes, we examined the role of S1P(1R) in the rejection response. Quantitative polymerase chain reaction (PCR) revealed strong expression of S1P(1R) messenger RNA (mRNA)on col(V)-reactive lymphocytes isolated from immunized rats. S1P(1R)-specific siRNA (S1P(1R) siRNA) reduced expression of S1P(1R) mRNA and protein, whereas scramble siRNA (SC siRNA) had no effect. Adoptive transfer of lymphocytes treated with S1P(1R) siRNA to rat Wistar Kyoto (WKY) lung isograft recipients resulted in retention of cells within the liver with fewer cells in mediastinal lymph nodes when compared to cells exposed to SC siRNA. S1P(1R)-deficient cells proliferated in response to alloantigens, but not in response to col(V), and produced less interferon (IFN)-gamma in response to col(V) compared to controls. Downregulating S1P(1R) did not affect production of interleukin (IL)-10and tumor necrosis factor (TNF)-alpha, or expression of adhesion molecules critical for migration, but prevented rejection pathology and lowered local levels of IFN-gamma post adoptive transfer. These data demonstrate novel roles of S1P(1R,) which include regulating emigration and modulating lymphocyte activation.

Safety and tolerability of sequential pegylated IFN-alpha2a and tenofovir for hepatitis B infection in HIV(+) individuals.

Chronic hepatitis B virus infections are a major cause of morbidity and mortality in HIV co-infected patients. The standard of care for treating HCV co-infection has been guided by major clinical trials, but the treatment of HBV co-infection has not been as thoroughly studied and the standard of care remains largely untested. The single pill formulation of tenofovir with emtricitabine has become a standard treatment approach in HBV co-infected patients. WU114 was a phase 1 clinical trial that examined the safety and tolerability of sequential treatment of HBV with pegylated interferon-alpha2a plus delayed-initiation tenofovir in HIV co-infected individuals. We postulated that initial HBV viral load reduction with pegylated interferon prior to initiation of nucleoside/nucleotide therapy would increase seroconversion events and durability of HBV virologic suppression. No severe pegylated IFN-alpha2a drug toxicities were seen in either the monotherapy or delayed tenofovir arms. Sequential pegylated interferon and tenofovir-based therapy was tolerable and should be compared with dual nucleoside/nucleotide suppression to determine relative frequencies of seroconversion and durability of HBV suppression in co-infected patients.

Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants.

Immunity to collagen V [col(V)] contributes to lung 'rejection.' We hypothesized that ischemia reperfusion injury (IRI) associated with lung transplantation unmasks antigenic col(V) such that fresh and well-healed lung grafts have differential susceptibility to anti-col(V)-mediated injury; and expression of the autoimmune cytokines, IL-17 and IL-23, are associated with this process. Adoptive transfer of col(V)-reactive lymphocytes to WKY rats induced grade 2 rejection in fresh isografts, but induced worse pathology (grade 3) when transferred to isograft recipients 30 days post-transplantation. Immunhistochemistry detected col(V) in fresh and well-healed isografts but not native lungs. Hen egg lysozyme-reactive lymphocytes (HEL, control) did not induce lung disease in any group. Col(V), but not HEL, immunization induced transcripts for IL-17 and IL-23 (p19) in the cells utilized for adoptive transfer. Transcripts for IL-17 were upregulated in fresh, but not well-healed isografts after transfer of col(V)-reactive cells. These data show that IRI predisposes to anti-col(V)-mediated pathology; col(V)-reactive lymphocytes express IL-17 and IL-23; and anti-col(V)-mediated lung disease is associated with local expression of IL-17. Finally, because of similar histologic patterns, the pathology of clinical rejection may reflect the activity of autoimmunity to col(V) and/or alloimmunity.

Expression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium.

The mRNA for Rvp.1 (rat ventral prostate) increases in abundance before gland involution after androgen deprivation. Rvp.1 is homologous to CPE-R, the high-affinity intestinal epithelial receptor for Clostridium perfringens enterotoxin (CPE), and is sufficient to mediate CPE binding and trigger subsequent toxin-mediated cytolysis. Rvp.1 (claudin-3) and CPE-R (claudin-4) are members of a larger family of transmembrane tissue-specific claudin proteins that are essential components of intercellular tight junction structures regulating paracellular ion flux. However, claudin-3 and claudin-4 are the only family members capable of mediating CPE binding and cytolysis. The present study was designed to study the expression of claudin-3 and claudin-4 in human prostate tissue as potential targets for CPE toxin-mediated therapy for prostate cancer. On human multiple-tissue Northern blot analysis, mRNAs for both claudin-3 and claudin-4 were expressed at high levels in prostate tissue. In normal prostate tissue, expression of claudin-3 was localized exclusively within acinar epithelial cells by in situ mRNA hybridization. Compared with expression within prostate epithelial cells in surrounding normal glandular tissue, expression of claudin-3 mRNA remained high in the epithelium of prostate adenocarcinoma (10 of 10) and prostatic intraepithelial neoplasia (five of five). Prostate adenocarcinoma cells metastatic to bone were obtained from a patient with disease progression during antiandrogen therapy. These metastatic cells were prostate-specific antigen-positive by immunohistochemical staining and also expressed functional CPE receptors as measured by sensitivity to CPE-induced cell lysis. The persistent high level of claudin-3 expression in prostate adenocarcinoma and functional cytotoxicity of CPE in metastatic androgen-independent prostate adenocarcinoma suggests a new potential therapeutic strategy for prostate cancer.

Obliterative muscularization of the small bowel submucosa in Crohn disease: a possible mechanism of small bowel obstruction.

CONTEXT: The pathology of small bowel obstruction in Crohn disease has not been studied extensively. Stricture formation has been attributed mainly to fibrosis, although muscularization of the submucosa has been discussed previously. OBJECTIVE: To identify additional pathologic changes in Crohn disease that could be involved in the formation of strictures. DESIGN: We reviewed 50 ileal resections from patients with Crohn disease. The histopathologic slides were reviewed initially without knowledge of the macroscopic or clinical findings. We identified an unusual muscular proliferation that we refer to as obliterative muscularization of the submucosa, defined as a thick and continuous muscle layer from the mucosal base to the muscularis propria that is at least 1 cm in length. Subsequently, histopathologic findings were correlated with macroscopic and clinical findings. RESULTS: Obliterative muscularization of the submucosa was present in 14 specimens, and in 11 of these 14 it was topographically restricted to strictures. Submucosal fibrosis was observed in sections from adjacent regions. Obliterative muscularization of the submucosa, including thick-walled vessels and hyperplastic nerves but not prominent scarring, was more common in specimens with strictures; the difference was statistically significant (P <.001). CONCLUSIONS: Obliterative muscularization of the submucosa may be pathogenetically involved in the formation of strictures either directly by causing a sustained spasm, or indirectly by minimizing the vasoprotective role of the submucosa, impairing repair and enhancing scarring.

Oral tolerance induction by type V collagen downregulates lung allograft rejection.

Immunization with specific proteins or peptides has been used to induce immunologic tolerance to allografts other than the lung. Recently, we have reported that the immune response to lung alloantigen also involves an immune response to type V collagen [col(V)]. The purpose of the current study was to determine if oral administration of col(V) to lung allograft recipients before transplantation downregulates acute rejection episodes. The data show that, compared with controls, col(V)-fed recipients had fewer polymorphonuclear cells and lymphocytes in allograft bronchoalveolar lavage fluid, and reduced rejection pathology. Data showing that col(V)- fed allograft recipients had diminished delayed-type hypersensitivity (DTH) responses to donor alloantigens suggest that feeding col(V) prevented allograft rejection by inducing tolerance to donor antigens. Systemic production of transforming growth factor (TGF)-beta, interleukin (IL)-4, or IL-10 has been reported to be a mechanism for oral tolerance-induced suppression of immune responses. Feeding col(V) induced upregulated production of TGF-beta, but not IL-4 or IL-10 in serum. Neutralizing TGF-beta recovered the DTH response to donor antigen in tolerant allograft recipients. Collectively, these data show that oral administration of col(V) is a novel approach to induce immunologic tolerance to lung allografts, and that TGF-beta contributed to suppression of the rejection response.

Interleukin-5 inhibition of biliary cell chloride currents and bile flow.

Recent studies have detected significant elevations of interleukin (IL)-5 mRNA in the liver parenchyma of patients with both primary biliary cirrhosis and acute rejection after liver transplantation. In both of these disorders, intrahepatic biliary epithelial cells (BECs) are the targets of injury. We hypothesized that BECs may themselves express IL-5 receptors that may modulate key biliary functions. RNAs coding for IL-5alpha and -beta receptors were amplified by RT/PCR from a biliary cell line derived from a human cholangiocarcinoma (Mz-ChA-1) and verified by DNA sequencing. IL-5 receptor distribution was detected immunocytochemically on Mz-ChA-1 cells, immortalized murine BEC, bile duct-ligated rat liver, and isolated cholangiocytes. Patch-clamp studies on Mz-ChA-1 cells showed that IL-5 inhibits 5'-N-ethylcarboxamidoadenosine-stimulated chloride currents. Additional functional studies showed that IL-5 inhibits secretin-induced bile flow. We conclude that BECs express IL-5 receptors and that IL-5 modulates BEC chloride currents and fluid secretion. Since IL-5 has previously been associated with cholestatic liver disease, we speculate that IL-5 may contribute to liver injury through its effects on biliary secretion.

Monocyte chemoattractant protein-1 and RANTES are chemotactic for graft infiltrating lymphocytes during acute lung allograft rejection.

Graft infiltrating lymphocytes (GILs) are crucial to rejection of lung allografts. However, chemotactic activities, chemokines responsible for GIL recruitment, and cells involved in chemokine production during lung allograft rejection have not been evaluated. This study determined whether chemotactic activity for GILs is upregulated, and whether the chemokines monocyte chemoattractant protein (MCP)-1 and regulated on activation, normal T cells expressed and secreted (RANTES) have roles in GIL chemotaxis during lung allograft rejection. F344 (RT1(lv1)) rat lung allografts were transplanted into WKY (RT1(l)) recipients. Chemotactic activity for GILs and quantities of MCP-1 and RANTES were determined in allograft bronchoalveolar lavage fluid 1 wk after transplantation. Data showed that during rejection, chemotactic activity for GILs is upregulated, MCP-1 and RANTES are produced locally, and both MCP-1 and RANTES are operative in GIL recruitment. Immunohistochemistry showed that alveolar macrophages (AMs) were the major source of MCP-1 and that other lung cells, including AMs, were the source of RANTES. Further, depletion of AMs in the donor lung before transplantation downregulated chemotaxis for GILs and production of MCP-1 during rejection episodes. These data show that chemotaxis for GILs is upregulated locally during lung allograft rejection, and that MCP-1 and RANTES contribute to GIL recruitment during the rejection response.

Pathology of the adenoma-carcinoma sequence: from aberrant crypt focus to invasive carcinoma.

The adenoma-carcinoma sequence postulates that colorectal carcinomas arise from precursor lesions, called adenomas. All adenomas contain dysplastic epithelium that arises from mutations in either the adenomatous polyposis coli gene or DNA mismatch repair genes. The earliest lesion detected with dysplasia is the aberrant crypt focus. Over time, as this lesion acquires additional mutations, it evolves into a classic adenomatous polyp. Adenomatous polyps are classified as tubular, tubulovillous, or villous. Generally, as polyps increase in size, the degree of dysplasia worsens, the villous component increases, the number of genetic abnormalities increases, and the likelihood of harboring invasive carcinoma increases. Carcinomas associated with DNA mismatch repair mutations are more likely to be poorly differentiated and incite a host lymphocytic response. These tumors seem to have a better prognosis, stage for stage, than typical colorectal carcinomas.

Instillation of allogeneic lung antigen-presenting cells deficient in expression of major histocompatibility complex class I or II antigens have differential effects on local cellular and humoral immunity and on pathology in recipient murine lungs.

Recognition of allogeneic major histocompatibility complex (MHC) molecules expressed on donor lung antigen-presenting cells (APCs) by host T lymphocytes is believed to stimulate lung allograft rejection. However, the specific roles of donor MHC molecules in the rejection response is unknown. We report a murine model in which instilling allogeneic lung APCs into recipient lungs induces pathology analogous to acute rejection, and the production of interferon (IFN)-gamma, immunoglobulin (Ig) G2a, and alloantibodies in recipient lungs. Using allogeneic lung APCs (C57BL/6, I-a(b), H-2(b)) deficient in MHC class I, II, or both for instillation into lungs of BALB/c mice (I-a(d), H-2(d)), the purpose of the current study was to determine the specific roles of donor MHC molecules in stimulating local alloimmune responses. The data show that MHC class I or II on donor APCs induced IFN-gamma and IgG2a synthesis locally, though less than that induced by wild-type cells. Both MHC class I and II were required to induce alloantibody production. Instillation of wild-type or class I- or class II-deficient APCs induced comparable pathologic lesions in recipient lungs, and more severe than that induced by MHC-deficient cells. These data show that donor MHC class I and II molecules have differential effects in the stimulation of local alloimmune responses.

Need for validation of clinical decision aids: use of the AST/ALT ratio in predicting cirrhosis in chronic hepatitis C.

OBJECTIVE: A value of > or = 1 for the ratio of aspartate amino-transferase to alanine aminotransferase (the AST/ALT ratio or AAR) has been shown to have a positive predictive value of 100% for the diagnosis of cirrhosis in patients with chronic hepatitis C. If validated on separate cohorts, an AAR > or = 1 might obviate the need for liver biopsy in some patients with hepatitis C. METHODS: We attempted to validate the AAR by abstracting demographic and clinical data from a database of consecutive patients with hepatitis C who had a liver biopsy between 1993 and 1998. We used definitions, methods of data collection, and analyses comparable to those of the published study. A hepatopathologist blindly reviewed 49 liver biopsies for histological grade and stage. RESULTS: The current cohort of 177 patients and the previous cohort of 139 patients were comparable in mean age (42.3 vs 43.8 yr), percentage of men (63 vs 67), percentage with an AAR > or =1 (20 vs 17), and Child-Pugh distribution, but differed in substantial use of ethanol (11% vs 3.6%; p = 0.01) and in the prevalence of cirrhosis (23% vs 34%, p = 0.06). Respective sensitivities of the AAR were 56% and 53%. An AAR > or =1 had a positive predictive value of 64% (95% confidence interval 48-78%) for the current cohort. Thirteen of 36 patients (36%) with an AAR > or =1 were incorrectly identified as having cirrhosis. Of these 13 patients, 6 had a normal AST and ALT, 5 had a minimally elevated AST or ALT, and 1 had advanced fibrosis without cirrhosis. CONCLUSIONS: These results suggest that an AAR > or =1 may not be as useful for predicting cirrhosis in chronic hepatitis C as previously thought, and emphasizes the need for validation of clinical decision aids on independent patient cohorts.

Type V collagen modulates alloantigen-induced pathology and immunology in the lung.

Perivascular and peribronchiolar tissues are targets of the immune response during lung allograft rejection. Collagen type V (col[V]) is located within these tissues. Col(V) may be major histocompatibility complex (MHC)-like, and MHC-derived peptides have been used to induce immunologic tolerance and prevent rejection in allografts other than the lung. The current study tests the hypothesis that col(V) could be used to downregulate immune responses to lung alloantigen in vivo. We developed a murine model in which instillations of allogeneic bronchoalveolar lavage (BAL) cells (C57BL/6, I-a(b), H-2(b)) into lungs of BALB/c mice (I-a(d), H-2(d)) induce histology similar to grades 1 and 2 acute lung allograft rejection, apoptosis of airway epithelium and vascular endothelium, and upregulate tumor necrosis factor (TNF)-alpha production locally. The current study reports that instillations of col(V) into lungs before allogeneic BAL cells prevent development of rejection pathology and apoptosis, downregulate alloantigen-induced T-lymphocyte proliferation, and abrogate local TNF-alpha production. In addition, instillation of col(V)-pulsed autologous BAL cells into lungs of mice primed with allogeneic BAL cells perpetuates rejection pathology. Collectively, these data show that col(V) is a novel antigen involved in the rejection process, and suggest that col(V) could be used to modulate the rejection response to lung allografts.

Screening colonoscopy in asymptomatic average-risk African Americans.

BACKGROUND: Recent data indicate that colorectal cancer incidence and mortality in white Americans have been declining since 1985 at a rate of 2% to 3% per year. In African Americans, however, mortality from colorectal cancer appears to be increasing. We sought to evaluate the prevalence of colonic neoplasia in asymptomatic African Americans. METHODS: We performed a cross-sectional colonoscopy screening study to determine the prevalence of colonic neoplasia in asymptomatic African Americans older than 50 years of age. RESULTS: One hundred sixty-six subjects were evaluated for the study of whom 121 (69 women) were deemed to be asymptomatic average-risk persons and completed colonoscopy. Forty-two individuals (35%) had a total of 72 adenomas (67 tubular and 5 tubulovillous); 47 (65.3%) of these were proximal to the splenic flexure. Three subjects had an adenoma 1 cm or greater in diameter and none had severe dysplasia. CONCLUSIONS: The overall prevalence of adenomas in asymptomatic average-risk African Americans was comparable to that of previously described populations. The predominance of right-sided adenomas in this study confirms previous findings and is an area requiring further study. Until this issue is resolved, we suggest the use of colonoscopy rather than sigmoidoscopy for screening for colorectal neoplasia in asymptomatic, average-risk African Americans.

Synovial sarcoma of the upper digestive tract: a report of two cases with demonstration of the X;18 translocation by fluorescence in situ hybridization.

Two cases of synovial sarcoma that arose in the upper digestive tract are reported. One case was a polypoid mass that arose at the gastroesophageal junction; the other was a large intramural mass that arose in the wall of the stomach. Both cases had a classic biphasic pattern. In the stomach tumor, the biphasic morphology was focal and there was an abrupt transition to poorly differentiated synovial sarcoma. The tumors had immunohistochemical features that were consistent with synovial sarcoma. Ultrastructural evaluation of the gastroesophageal tumor supported the diagnosis. The diagnostic X;18 translocation was demonstrated by fluorescence in situ hybridization on sections from paraffin-embedded tissue in 86% and 50% of interphase nuclei from the gastroesophageal and gastric tumor, respectively. The translocation was present in equal frequency in the epithelial and spindle cells in the biphasic areas and the poorly differentiated areas of the gastric tumor, indicating that the development of the more aggressive subclone was probably due to genetic mutations not encompassing the SYT-SSX gene fusion product. We are aware of only five reported cases of synovial sarcoma arising in the digestive tract, all in the proximal esophagus. These cases are the first reported arising in the gastroesophageal junction and stomach and the only cases of synovial sarcoma of the digestive tract in which the diagnostic translocation was demonstrated. Sarcomatoid carcinoma (carcinosarcoma) and gastrointestinal stromal tumor are the main differential diagnoses for synovial sarcoma in this site. Synovial sarcoma of the digestive tract may be underdiagnosed, and its recognition may have important clinical implications. Fluorescence in situ hybridization is helpful in making this distinction.

Allelotype of gastric adenocarcinoma.

Gastric adenocarcinoma is a leading cause of cancer mortality world-wide. Yet, the underlying molecular events important in the development of this cancer are largely undefined. Thus, we performed a comprehensive survey for allelic loss on our panel of xenografted human gastric carcinomas. Contaminating normal stromal cells of primary cancers often limit mutational analyses. Xenografted samples of our gastric carcinomas provided optimally enriched tumors for neoplasia that clearly and sensitively demonstrated genetic alterations. Additionally, total absence of allelic signals in these xenografted samples confirmed true loss of alleles rather than just allelic imbalance. Analysis of at least two highly polymorphic microsatellite markers per nonacrocentric chromosomal arm in our xenografted human gastric carcinomas demonstrated significant loss of heterozygosity well above background levels at 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q. Several of these loci represent novel findings of significant loss in gastric cancers. On chromosome 17p, p53 is known to be inactivated either by mutation or deletion in a majority of gastric carcinomas. The critical target(s) of inactivation in gastric cancers at these other loci remain to be characterized.

Allogeneic bronchoalveolar lavage cells induce the histology and immunology of lung allograft rejection in recipient murine lungs: role of intercellular adhesion molecule-1 on donor cells.

BACKGROUND: Intercellular adhesion molecule (ICAM)-1 expressed on accessory cells has a key role in antigen presentation. The histology and immunology of lung allograft rejection is postulated to result from donor lung accessory cells presenting alloantigens to recipient lymphocytes, and, therefore, ICAM-1 may have a crucial role in the rejection process. We have previously reported that the instillation of allogeneic (C57BL/6, I-a(b)) bronchoalveolar lavage (BAL) cells (96% macrophages, 2% dendritic cells) into the lungs of recipient BALB/c mice (I-a(d)) induced the histology and immunology of acute lung allograft rejection. Using this model, the purpose of the current study was to determine the role of ICAM-1 on donor lung cells in lung allograft rejection. METHODS: BALB/c mice received allogeneic BAL cells from wild-type or ICAM-1 mutant (lacking ICAM-1 expression) C57BL/6 mice by nasal insufflation weekly for 4 weeks. Recipient mice underwent BAL and serum collection for the determination of T helper 1/T helper 2 cytokines and IgG subtypes. Lung histology was graded using standard criteria for allograft rejection. RESULTS: Although wild-type cells induced a lymphocytic vasculitis and bronchitis, ICAM-1 mutant allogeneic BAL cells only induced a lymphocytic vasculitis in recipient lungs. Both wild-type and ICAM-1 mutant cells induced up-regulated local interferon-gamma and IgG2a production, and deposition of IgG2a in recipient lungs. CONCLUSIONS: These data show that ICAM-1 on donor lung accessory cells mediates differential effects on the histology and immunology of acute lung allograft rejection.

Evolution of acute cytomegalovirus gastritis to chronic gastrointestinal dysmotility in a nonimmunocompromised adult.

A 30-year-old nonimmunocompromised woman developed chronic gastrointestinal dysmotility as a consequence of acute cytomegalovirus infection. The acute nature of the infection was documented by high immunoglobulin M antibody titer to cytomegalovirus (CMV); the chronicity of the infection was shown by persistence of CMV in biopsy specimens of her gastrointestinal tract over a 21/2-year period. Gastrointestinal dysmotility was confirmed by delayed emptying on gastric nuclear scintigraphy, by retrograde propagation of migrating myoelectric complexes on small intestinal manometry, and by presence of tachygastria on cutaneous electrogastrography. The patient's nausea, vomiting, abdominal pain, and early satiety resolved after a short course of treatment with leuprolide acetate but returned after medication was discontinued. Her symptoms persisted despite clearance of CMV from the gastrointestinal tract after a course of treatment with ganciclovir. These observations show that acute CMV infection can cause gastrointestinal dysmotility in nonimmunocompromised individuals and that the disturbance in gastrointestinal motor function may persist for years after viral infection of the gastrointestinal tract has been eradicated.